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Background: Tobacco smoking is the largest preventable cause of morbidity and premature mortality in the world. Although its medical consequences are well documented, 20–50% of the population even in developed countries remain tobacco smokers. The drugs presently used in smoking cessation have limited efficiency and, therefore, there is a need for alternative and improved treatments. One novel approach in this regard may be provided by immunization against nicotine. Objective: The present study in male Wistar rats investigated if active immunization with a novel nicotine immunogen, IP18-KLH, may generate nicotine-selective antibodies and, furthermore, whether this treatment might prevent nicotine from exerting its stimulating effect on the mesolimbic, dopaminergic reward system in the brain. Methods: Enzyme-linked immunosorbent assay (ELISA) was used to determine the titer of nicotine antibodies in plasma after immunization with IP18-KLH in Freund’s adjuvant. Competitive ELISA was used to assess the selectivity of the antibodies. Finally, we used in vivo voltammetry to investigate whether active immunization with IP18-KLH could prevent nicotine-induced dopamine release in the shell of nucleus accumbens (NAC_shell). Results: The present study shows that active immunization with IP18-KLH generates antibodies that are highly selective for nicotine. Furthermore, immunization with IP18-KLH prevented the nicotine-induced increase in dopamine release in the NAC_shell, a biochemical correlate to the rewarding properties of nicotine. Conclusions: Active immunization with IP18-KLH prevents a central effect of nicotine that is considered critical for the induction of nicotine dependence. Consequently, active immunization may provide long-term protection against initiation of tobacco dependence, an effect that may prove particularly advantageous in relapse prevention.

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Antidepressant drugs are frequently used to treat affective symptoms in schizophrenia. We have recently shown that escitalopram, but not citalopram or R-citalopram, increases firing rate and burst firing of midbrain dopamine neurons, potentiates cortical N-methyl-D-aspartate (NMDA) receptor-mediated transmission and enhances cognition, effects that might influence the outcome of concomitant antipsychotic medication. Here, we studied, in rats, the behavioral and neurobiological effects of adding escitalopram, citalopram, or R-citalopram to the second-generation antipsychotic drug risperidone. We examined antipsychotic efficacy using the conditioned avoidance response (CAR) test, extrapyramidal side effect (EPS) liability using a catalepsy test, dopamine outflow in the medial prefrontal cortex (mPFC) and nucleus accumbens using in vivo microdialysis in freely moving animals, and NMDA receptor-mediated transmission in the mPFC using intracellular electrophysiological recording in vitro. Only escitalopram (5 mg/kg), but not citalopram (10 mg/kg), or R-citalopram (10 mg/kg), dramatically enhanced the antipsychotic-like effect of a low dose of risperidone (0.25 mg/kg), without increasing catalepsy. Given alone, escitalopram, but not citalopram or R-citalopram, markedly enhanced both cortical dopamine output and NMDA receptor-mediated transmission. Addition of escitalopram and to some extent R-citalopram, but not citalopram, significantly enhanced both cortical dopamine output and cortical NMDA receptor-mediated transmission induced by a suboptimal dose/concentration of risperidone. These results suggest that adjunct treatment with escitalopram, but not citalopram, may enhance the effect of a subtherapeutic dose of risperidone on positive, negative, cognitive, and depressive symptoms in schizophrenia, yet without increased EPS liability.

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We have previously shown that the nicotine-induced dopamine release in the nucleus accumbens can be attenuated by local administration into the ventral tegmental area (VTA), of antagonists at nicotinic and N-methyl-D-aspartate (NMDA), but not alpha-amino-3-hydroxy-5-methylisoxazole-4-propionate (AMPA) receptors. In the present study, we investigated the role of nicotinic and NMDA receptors in the VTA for the expression of Fos-like immunoreactivity (FLI) in the shell and core of the nucleus accumbens and in the medial prefrontal cortex (mPFC) of the rat after acute nicotine administration. Systemically administered nicotine increased FLI in both the mPFC and the nucleus accumbens when compared to saline controls, although this effect was more pronounced, and reached statistical significance in the nucleus accumbens, especially in the core region. When mecamylamine was delivered by reverse dialysis into the VTA, the systemic nicotine-induced FLI was significantly attenuated in the nucleus accumbens. Similarly, the NMDA receptor antagonist 2-amino-5-phosphonopentanoic acid (AP-5), infused locally in the VTA, also antagonized the nicotine-induced FLI in the nucleus accumbens. Neither mecamylamine nor AP-5 alone affected basal FLI levels in any of the structures studied. Local administration of nicotine in the VTA increased FLI in the nucleus accumbens but not in the mPFC. Since the nicotine-induced FLI is probably due to an increased dopamine release in both the nucleus accumbens and the mPFC, we conclude that FLI in the nucleus accumbens is mediated, to a large extent, through the activation of dopamine neurons via nicotinic and NMDA receptors in the VTA, whereas the nicotine-induced FLI in the mPFC is subjected to a differential control mechanism, tentatively involving nicotinic receptors at the terminal level of the mPFC-projecting dopamine neurons.

Our results suggest that the AMPA-PAMs, when compared to the GlyT-1 inhibitor, show differential effects in terms of augmentation of antipsychotic efficacy, particularly when combined with risperidone or olanzapine. Both AMPA-PAMs and the GlyT-1 inhibitor may also improve negative symptoms and cognitive impairments in schizophrenia, in particular when combined with risperidone.